Ophthalmic compositions containing galactomannan polymers and borate

ABSTRACT

The present invention is directed to ophthalmic compositions containing a gelling amount of a combination of galactomannan polysaccharides and borates. The compositions gel or partially gel upon administration to the eye. The present invention also discloses methods of topical ophthalmic administration of the compositions of the eye.

This application claims priority from provisional application Ser. No.60/054,132, filed Jul. 29, 1997.

BACKGROUND OF THE INVENTION

The present invention relates to the use of adjuvants in topicalophthalmic compositions. In particular, the present invention relates topharmaceutical compositions comprising galactomannan polymers incombination with borates, and methods for the controlled administrationof pharmaceutically active agents to patients, wherein the compositionsare administered as liquids which thicken to form gels upon instillationinto the eye. The transition from liquid to gel is primarily due to thechange in pH and ionic strength.

Topical ophthalmic compositions have taken the form of liquids,ointments, gels and inserts. Liquid compositions for drop-wiseinstillation of pharmaceutically active agents to the eve provide foreasy administration, but they do not always provide for an accuratedosage amount, as portions of the liquid are often blinked away duringadministration or drained down the punctum into the nasal passage.Ointments and gels, which usually reside in the eye longer than a liquidand therefore provide for more accurate administration, often interferewith a patient's vision. Ocular inserts, both bioerodible andnon-bioerodible, are also available and allow for less frequentadministration of drug. These inserts, however, require complex anddetailed preparation and are frequently uncomfortable to the wearer. Anadditional problem with non-bioerodible inserts is that they must beremoved after use.

U.S. Pat. No. 4,136,173 (Pramoda, et al.) discloses the use oftherapeutic compositions containing xanthan gum and locust bean gumwhich are administered in liquid form and gel upon instillation. Thisreference describes a mechanism for transition from liquid to gelinvolving pH change. pH sensitive gels such as carbomers, xanthan,gellan, and those described above, need to be formulated at or below thepKa of their acidic groups (typically at a pH of about 2 to 5).Compositions formulated at low pH, however, are irritating to the eye.

The use of locust bean gum to form a gel vehicle for ophthalmic drugdelivery is described in U.S. Pat. No. 4,136,177 (Lin, et al.). However,the gels described by Lin, et al. are formed at the time of manufacture,rather than upon application to the eye.

U.S. Pat. No. 4,861,760 (Mazuel, et al.) discloses ophthalmiccompositions containing gellan gum which are administered to the eye asnon-gelled liquids and gel upon instillation due to a change in ionicstrength. These systems do not involve the use of small cross-linkingmolecules, but instead provide gel characteristics due to selfcross-linking during ionic condition changes.

Gels involving the cross-linking of polysaccharides wit h borates aredisclosed for use as well fracturing fluids in U.S. Pat. No. 5,082,579(Dawson), U.S. Pat. No. 5,145,590 (Dawson), and U.S. Pat. No. 5,160,643(Dawson). These patents describe the use of borates and polysaccharidesfor industrial oil well excavation.

The ophthalmic use of current gelling liquid systems have a number ofdrawbacks. For example, natural polymers such as xanthan gum have thedisadvantage of lot to lot variability due to variations in sourceand/or limited manufacturing controls during processing. Thesevariabilities cause significant undesirable changes in the properties ofthe compound, such as variable gelling characteristics. Thermogellingsystems such as polyethylene oxide/polypropylene oxide block copolymers(“PEO/PPO”) lose water in order to form gels, and consequently result inturbid gels. Polyvinyl alcohol (“PVA”)-borate combination gellingsystems need to be formulated at low pH, and therefore, can cause ocularirritation upon instillation. Other gelling systems have viscosity,rehydration and cloud point instability problems associated withautoclaving.

Polyvinyl alcohol crosslinking with borates have been disclosed in U.S.Pat. No. 4,255,415 (Sukhbir et al.). These compositions are pre-formedgels, and are therefore hard to dispense. WIPO Publication No. WO94/10976 (Goldenberg et al.) discloses a low pH PVA-borate deliverysystem that does go through liquid/gel transition. This system has thedisadvantage, however, of limited gelling effects, and only at certainconcentrations of PVA depending on the molecular weight of the PVAutilized. Furthermore, since the crosslinking cites are unlimited withthis system, strong local gelation upon addition of base has limited itsmanufacturing, and therefore, polyvinyl pyrrolidone presumably has beenincluded in these compositions to overcome the shortcoming. The novelgelling system of the present invention does not have the abovelimitation.

SUMMARY OF THE INVENTION

The present invention is directed to topical ophthalmic compositionscomprising galactomannan polymers and borate compounds which providecontrolled administration of a drug to the eye. The invention is basedon a new gelling system which comprises a galactomannan polysaccharideand a borate crosslinker which forms a gel upon increases in pH andionic strength. In this novel system, bisdiol borates crosslink with thecis diol groups of the sugar moieties of the polysaccharide. Thecompositions are administered as liquids or partially gelled liquids(hereinafter “liquids”) which thicken to form gels upon instillationinto the eye. Alternatively, the compositions may not contain apharmaceutically active agent, and can be administered to the eye forlubrication or to supplement tears in the treatment of, for example, dryeye.

The present invention galactomannan-borate gelling system has severaladvantages over other gelling systems. One advantage is that thecompositions of the present invention are clear solutions and theresultant gel is also crystal clear. While other systems may becomeopaque or cloudy upon instillation, the crystal clear gel of the presentinvention provides greater clarity of vision to the treated eye. Thepresent invention compositions may be formulated at slightly acidic toneutral pH and require only a minor pH change to activate gelation(i.e., about 0.5 to 1.0 pH unit). This feature minimizes possibleirritation of the eye resulting from acidic exposure, such as may resultwith other pH sensitive systems which require a pH change of about 2.4to about 4.4 pH units (i.e., are formulated with a pH of about 3-5).Galactomannan polymers are also heat stable and show no cloud point evenduring autoclaving conditions. As such, viscosity and rehydrationproblems resulting from batch scale up, such as exist with PVA andcarbomer polymer systems, are not present with the galactomannan polymercontaining compositions of the present invention.

Galactomannan polysaccharides are non-ionic and, in combination withborates at acidic to neutral pH, are also essentially non-ionic. Thus,the polymer system is completely compatible with anionic, neutral andcationic drugs. Furthermore, the preservative efficacy of thepreservatives are not compromised by the presence of the polymer.Typically, the efficacy of benzalkonium chloride or other cationicpreservatives are compromised with anionic polymers such as gellan andcarageenan, and excess preservative may therefore be needed in thosesystems. Increases in preservative concentration may also increaseirritation and toxicity of the composition.

The galactomannan-borate gelling system of the present invention hasother advantages. Galactomannan polymers have a relatively low molecularweight and are therefore easy to manufacture and scale up. Galactomannanpolymers are also readily available and have been used in food andpersonal care products such that the polymers are considered to be safe.Furthermore, control or manipulation of the gelling characteristics ofthe galactomannan-borate gelling compositions of the present inventionis relatively simple as compared with prior art systems. The gellingproperties of other single polymer systems, such as ionomers, e.g.,gellan and carageenans, and thermogels, e.g., poloxamines andpoloxamers, are typically related to the molecular weight and the numberof functional groups of the polymers. Thus, in order to change the gelpoint or degree of gelation of those prior art systems, one would needto modify the base polymer—a labor intensive activity. In contrast, bysimply manipulating the borate to galactomannan ratio in the presentinvention compositions, a wide range of gelling characteristics isavailable in order to fine tune the compositions to the targetedrequirements (see FIGS. 1 and 2). Moreover, as illustrated in FIG. 3,the galactomannans of the present invention (e.g., guar gum) demonstrateexcellent gelling consistency and reproducibility, though the type orsource of the galactomannan is varied.

Still other advantages are present in the compositions of the presentinvention. The galactomannan polymer and the borate crosslinkercompositions of the present invention are liquids and, therefore, easyto dispense. Some gelling systems such as gellan gum, as disclosed inU.S. Pat. No. 4,861,760 (Mazuel et al.), are thixotropic, which mayrequire shaking to increase the fluidity and ease of dispensing. Thepresent invention compositions contain a relatively low concentration ofgalactomannan (about 0.2 to 0.5%) as compared to some thermogellingsystems such as PEO/PPO block copolymers, which require very highconcentrations. Lower concentrations of the gelling polymer providelower potential toxicity and ease of preservation from microbialcontamination over higher concentration systems.

The methods of the present invention involve the topical administrationof the galactomannan-borate containing compositions of the presentinvention.

The present invention is also directed to methods of sterilization ofthe galactomannans involving autoclaving.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the gelling characteristics of variousconcentrations of guar gum in the presence of borate, relative to pH.

FIG. 2 is a graph illustrating the gelling characteristics of variousconcentrations of borate in the presence of guar gum, relative to pH.

FIG. 3 is a graph illustrating the uniformity of the gellingcharacteristics of three different types/sources of guar gum.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to ophthalmic compositions whichcomprise one or more galactomannan polysaccharide(s) and one or moreborate compound(s). The present invention is also directed to methods ofusing these compositions to treat various ophthalmic disorders includingdry eye, glaucoma, ocular hypertension, infection, allergy andinflammation.

The types of galactomannans that may be used in the present inventionare typically derived from guar gum, locust bean gum and tara gum. Asused herein, the term “galactomannan” refers to polysaccharides derivedfrom the above natural gums or similar natural or synthetic gumscontaining mannose or galactose moieties, or both groups, as the mainstructural components. Preferred galactomannans of the present inventionare made up of linear chains of (1-4)-β-D-mannopyranosyl units withα-D-galactopyranosyl units attached by (1-6) linkages. With thepreferred galactomannans, the ratio of D-galactose to D-mannose varies,but generally will be from about 1:2 to 1:4. Galactomannans having aD-galactose:D-mannose ratio of about 1:2 are most preferred.Additionally, other chemically modified variations of thepolysaccharides are also included in the “galactomannan” definition. Forexample, hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropylsubstitutions may be made to the galactomannans of the presentinvention. Non-ionic variations to the galactomannans, such as thosecontaining alkoxy and alkyl (C1-C6) groups are particularly preferredwhen a soft gel is desired (e.g., hydroxylpropyl substitutions).Substitutions in the non-cis hydroxyl positions are most preferred. Anexample of non-ionic substitution of a galactomannan of the presentinvention is hydroxypropyl guar, with a molar substitution of about 0.4.Anionic substitutions may also be made to the galactomannans. Anionicsubstitution is particularly preferred when strongly responsive gels aredesired.

The borate compounds which may be used in the compositions of thepresent invention are boric acid and other pharmaceutically acceptablesalts such as sodium borate (borax) and potassium borate. As usedherein, the term “borate” refers to all pharmaceutically suitable formsof borates. Borates are common excipients in ophthalmic formulations dueto good buffering capacity at physiological pH and well known safety andcompatibility with a wide range of drugs and preservatives. Borates alsohave inherent bacteriostatic and fungistatic properties, and thereforeaid in the preservation of the compositions.

The present invention compositions comprise one or more galactomannan(s)in the amount of from about 0.1 to 5% weight/volume (“w/v”) and boratein the amount of from about 0.05 to 5% (w/v). Preferably, thecompositions will contain 0.2 to 2.0% (w/v) of galactomannan and 0.1 to2.0% (w/v) of a borate compound. Most preferably, the compositions willcontain 0.3 to 0.8% (w/v) of galactomannan and 0.25 to 1.0% (w/v) of aborate compound. The particular amounts will vary, depending on theparticular gelling properties desired. In general, the borate orgalactomannan concentration may be manipulated in order to arrive at theappropriate viscosity of the composition upon gel activation (i.e.,after administration). As shown in FIGS. 1 and 2, manipulating eitherthe borate or galactomannan concentration provides stronger or weakergelation at a given pH. If a strongly gelling composition is desired,then the borate or galactomannan concentration may be increased. If aweaker gelling composition is desired, such as a partially gellingcomposition, then the borate or galactomannan concentration may bereduced. Other factors may influence the gelling features of thecompositions of the present invention, such as the nature andconcentration of additional ingredients in the compositions, such assalts, preservatives, chelating agents and so on. Generally, preferrednon-gelled compositions of the present invention, i.e., compositions notyet gel-activated by the eye, will have a viscosity of from about 5 to1000 cps. Generally, preferred gelled compositions of the presentinvention, i.e., compositions gel-activated by the eye, will have aviscosity of from about 50 to 50,000 cps.

The galactomannans of the present invention may be obtained fromnumerous sources. Such sources include guar gum, locust bean gum andtara gum, as further described below. Additionally, the galactomannansmay also be obtained by classical synthetic routes or may be obtained bychemical modification of naturally occurring galactomannans.

Guar gum is the ground endosperm of Cyamopisis tetragonolobus (L.) Taub.The water soluble fraction (85%) is called “guaran” (molecular weight of220,000), which consists of linear chains of (1-4)-β-D mannopyranosylunits with α-D-galactopyranosyl units attached by (1-6) linkages. Theratio of D-galactose to D-mannose in guaran is about 1:2. The gum hasbeen cultivated in Asia for centuries and is primarily used in food andpersonal care products for its thickening property. It has five to eighttimes the thickening power of starch. Its derivatives, such as thosecontaining hydroxypropyl or hydroxypropyltrimonium chloridesubstitutions, have been commercially available for over a decade. Guargum may be obtained, for example, from Rhone-Polulenc (Cranbury, N.J.),Hercules, Inc. (Wilmington, Del.) and TIC Gum, Inc. (Belcamp, Md.).

Locust bean gum or carob bean gum is the refined endosperm of the seedof the carob tree, ceratonia siliqua. The ratio of galactose to mannosefor this type of gum is about 1:4. Cultivation of the carob tree is oldand well known in the art. This type of gum is commercially availableand may be obtained from TIC Gum, Inc. (Bekamp, Md.) and Rhone-Polulenc(Cranbury, N.J.).

Tara gum is derived from the refined seed gum of the tara tree. Theratio of galactose to mannose is about 1:3. Tara gum is not produced inthe United States commercially, but the gum may be obtained from varioussources outside the United States.

In order to limit the extent of cross-linking to provide a softer gelcharacteristic, chemically modified galactomannans such as hydroxypropylguar may be utilized. Modified galactomannans of various degree ofsubstitution are commercially available from Rhone-Poulenc (Cranbury,N.J.). Hydroxypropyl guar with low molar substitution (e.g., less than0.6) is particularly preferred.

Other ingredients may be added to the compositions of the presentinvention. Such ingredients generally include tonicity adjusting agents,chelating agents, active pharmaceutical agent(s), solubilizers,preservatives, pH adjusting agents and carriers. Other polymer ormonomeric agents such as polyethylene glycol and glycerol may also beadded for special processing. Tonicity agents useful in the compositionsof the present invention may include salts such as sodium chloride,potassium chloride and calcium chloride; non-ionic tonicity agents mayinclude propylene glycol and glycerol; chelating agents may include EDTAand its salts; solubilizing agents may include Cremophor EL® and tween80; other carriers may include amberlite® IRP-69; pH adjusting agentsmay include hydrochloric acid, Tris, triethanolamine and sodiumhydroxide; and suitable preservatives may include benzalkonium chloride,polyquaternium-1 and polyhexamethylene biguanide. The above listing ofexamples is given for illustrative purposes and is not intended to beexhaustive. Examples of other agents useful for the foregoing purposesare well known in ophthalmic formulation and are contemplated by thepresent invention.

Combination of the gelling system of the present invention with priorart gelling systems is also contemplated by the present invention. Suchsystems may include the inclusion of ionomers, such as xanthan, gellan,carageenan and carbomers, and thermogels, such as ethylhydroxyethylcellulose.

In general, the compositions of the present invention will be used toadminister various pharmaceutically active compounds to the eye. Suchpharmaceuticals may include, but are not limited to, anti-hypertensive,anti-glaucoma, neuro-protective, anti-allergy, muco-secretagogue,angiostatic, anti-microbial, pain relieving and anti-inflammatoryagents.

Examples of pharmaceutically active agents which may be included in thecompositions of the present invention, and administered via the methodsof the present invention include, but are not limited to: glaucomaagents, such as betaxolol, timolol, pilocarpine, carbonic anhydraseinhibitors and prostglandins; dopaminergic antagonists; post-surgicalantihypertensive agents, such as para-amino clonidine (apraclonidine);anti-infectives, such as ciprofloxacin and tobramycin; non-steroidal andsteroidal anti-inflammatories, such as naproxen, diclofenac, suprofen,ketorolac, tetrahydrocortisol and dexamethasone; proteins; growthfactors, such as epidermal growth factor; and anti-allergics.

Optionally, the compositions of the present invention may be formulatedwithout a pharmaceutically active compound. Such compositions may beused to lubricate the eye or provide artificial tear solutions to treat,for example, dry eye. In general, artificial tear solutions will containtonicity agents, polymers and preservatives, as described above. Theamount of galactomannan and borate contained in the artificial tearsolutions will vary, as described above, but will generally be in theamount of from 0.1 to 3.0% (w/v) and 0.1 to 2.0% (w/v), respectively.

In general, the compositions of the present invention are formulated intwo parts. The galactomannan polymer is hydrated and sterilized (PartI). Any pharmaceutical agent(s) and/or other ingredients to be includedin the composition are then dissolved in water and sterile filtered(Part II). Parts I and II are then combined and the pH of the resultantmixture is adjusted to the target level, generally 6.0 to 7.0. If thepharmaceutical agent(s) to be included have low water solubility, theywill generally be added last. In certain cases, it may be preferred tosterilize the pharmaceutical agent(s) separately, and then aspeticallyadd the agent(s) and other ingredients together.

Sterilization of the galactomannan polysaccharide can be accomplished byautoclaving. Since the polymers undergo depolymerization at the extremeconditions of autoclaving, non-aqueous autoclaving is generallypreferred. This can be accomplished by dispersing the polymer in asuitable organic liquid such as low molecular weight polyethyleneglycols. The resulting suspension may then be autoclaved to sterilizethe polymer. The sterilized polymer is then hydrated aseptically, priorto admixture with the other ingredients.

The following example illustrates a novel method of sterilizing agalactomannan polysaccharide of the present invention:

EXAMPLE 1

Preliminarily, a compounding vessel (20 L stainless steel pressure can),a 0.2 micron sterilizing filter, a receiving vessel (20 L carboy), a 4.5micron polishing filter, a 0.2 micron sterilizing filter, a vent filter,and the filling equipment are sterilized by autoclaving.

In a beaker equipped with an overhead agitator, add the weighed amountof polyethylene glycol 400 (200 g). While mixing slowly disperse theweighed amount of hydroxypropyl (“HP”)Guar gum (10 g). Mix untilcompletely homogeneous. In a 500 ml Schott bottle, equipped with amagnetic stir bar, weigh exactly 120.0 g of the HPGuar gum/PEG-400dispersion. Prepare to sterilize by autoclaving. In a second identical500 ml Schott bottle weigh exactly 120.0 g of the same dispersion.Prepare to use as a dummy during the autoclaving cycle. To both bottlesadd 1.3 ml of purified water (amount equivalent, by volume, of themicroorganism suspension used to inoculate the bottles during thevalidation study). Mix both bottles for 10 minutes using a magnetic stirplate. Autoclave the HPGuar gum/PEG-400 dispersion using the validatedtime-temperature cycle of 80 minutes at 125° C.

The other set of ingredients to be included in the final formulation maybe prepared separately by various methods known in the art. Theresultant mixture can be added by sterile filtration to the compoundingvessel, along with the HPGuar gum/PEG-400 preparation.

Aseptically transfer the sterilized HPGuar gum/PEG400 dispersion intothe pre-sterilized compounding vessel. Rinse the bottle content withsterilized purified water. Bring the content of the compounding vesselto exactly 95% of the theoretical batch weight (19.0 liters or 19.06 Kg)using sterile room temperature purified water. Allow the HPGuar gum/PEGslurry to hydrate while mixing, at moderate speed, in the compoundingvessel for a minimum of 2 hours. Transfer the contents of thecompounding vessel through a 4.5 micron pre-sterilized polishing filterinto the pre-sterilized receiving vessel equipped with a stir bar. Therewill be some loss of the contents due to the product held in filterhousing and filter cartridge. (If a pressure can is used as compoundingvessel, the recommended pressure for clarification filtration isapproximately 30 psi.) Check and adjust pH, if necessary, to 6.9-7.1(target 7.0) using 1N NaOH or 1N HCl. Approximately 3-4 ml of 1N NaOHper 1 liter of final batch weight is needed to achieve the desired pH.QS to final batch weight using sterile purified water. Mix at low speedfor a minimum of 30 minutes.

The following examples further illustrate preferred ophthalmiccompositions of the present invention:

EXAMPLE 2

The following is an example of a topical ophthalmic compositioncontaining timolol.

Compound Amount % (w/v) Timolol Maleate 0.68* Boric Acid 0.5 Guar Gum0.5 PEG-400 1.0 Sodium Chloride 0.5 Benzalkonium Chloride 0.01 SodiumHydroxide/Hydrochloric Acid QS to pH 6.5 Purified Water QS *0.68%Timolol Maleate is equivalent to 0.5% Timolol.

The above formulation is prepared by first preparing a Part I and PartII mixture. The guar gum is first dispersed in PEG-400 and autoclaved asPart I. The other ingredients are dissolved in about 90% of the volumeof water and sterile filtered in a receiving vessel as Part II. Part Iis then added to Part II aseptically. The pH may then be adjustedaseptically and the batch is then brought to final weight (volume). Thecombined solution is then passed through a 1.0 μm polish filter,aseptically, to remove the particulates.

EXAMPLE 3

The following is another example of a topical ophthalmic compositioncontaining timolol.

Compound Amount % (w/v) Timolol Maleate 0.34* Boric Acid 0.5 Guar Gum0.25 Glycerol 1.0 Benzalkonium Chloride 0.005 SodiumHydroxide/Hydrochloric Acid QS to pH 7.0 Purified Water QS *0.34%Timolol Maleate is equivalent to 0.25% Timolol.

The above composition may be prepared in a similar way as the Example 2composition.

EXAMPLE 4

The following is an example of an artificial tear solution.

Compound Amount % (w/v) Boric Acid 0.5 Hydroxpropyl Guar 0.3 Propyleneglycol 1.4 Polyquaternium-1 0.0005 Sodium Hydroxide/Hydrochloric Acid QSto pH 6.8 Purified Water QS

The above composition may be prepared in a similar way as the Example 2composition.

The invention in its broader aspects is not limited to the specificdetails shown and described above. Departures may be made from suchdetails within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing itsadvantages.

What is claimed is:
 1. A topical ophthalmic composition in the form of aliquid, said liquid composition comprising 0.1 to 5% (w/v) guar or aderivative thereof, 0.05 to 5.0% (w/v) of a borate compound, and water,said liquid composition having a pH such that the liquid compositionthickens to form a gel or partial gel when one or more drops of theliquid composition are topically administered to the eye.
 2. A topicalophthalmic composition of claim 1, wherein the composition has aslightly acidic to neutral pH.
 3. A topical ophthalmic composition ofclaim 1, wherein the borate compound is selected from the groupconsisting of boric acid, sodium borate, potassium borate andcombinations thereof.
 4. A topical ophthalmic composition of claim 3,wherein the composition contains hydroxypropyl guar.
 5. A topicalophthalmic composition of claim 4, wherein the hydroxypropyl guar has amolar substitution of less than 0.6.
 6. A topical ophthalmic compositionof claim 4, wherein the borate compound comprises boric acid.
 7. Atopical ophthalmic composition of claim 6, wherein the compositioncomprises hydroxypropyl guar in a concentration of 0.2 to 2.0% (w/v) andboric acid in a concentration of 0.1 to 2.0% (w/v).
 8. A topicalophthalmic composition of claim 1, wherein the composition furthercomprises one or more pharmaceutically active agents.
 9. A topicalophthalmic composition of claim 8, wherein the pharmaceutically activeagent is selected from the group consisting of: anti-hypertensive,anti-glaucoma, neuro-protective, anti-allergy, muco-secretagogue,angiostatic, anti-microbial, pain-relieving and anti-inflammatoryagents.
 10. A topical ophthalmic composition of claim 1, wherein thecomposition has a pH of 6.0 to 7.0.
 11. A composition according to anyone of the claims 1-9, wherein the composition has a pH of 6.0 to 7.0.12. A composition according to any one of claims 1-10 wherein thecomposition is adapted for use as an ocular lubricant or artificial tearcomposition.
 13. A method of lubricating the eye, which comprisestopically applying a composition of any one of claims 1-10 to the eye.14. A sterile ophthalmic pharmaceutical composition, comprising 0.1 to5% (w/v) of a galactomannan selected from the group consisting of guarand derivatives thereof, 0.05 to 5.0% (w/v) of a borate compound, andwater.
 15. A sterile ophthalmic composition according to claim 14,wherein the borate compound is selected from the group consisting ofboric acid, sodium borate, potassium borate and combinations thereof.16. A sterile ophthalmic composition according to claim 15, wherein thegalactomannan comprises hydroxypropyl guar.
 17. A sterile ophthalmiccomposition according to claim 16, wherein the borate compound comprisesboric acid.
 18. A sterile ophthalmic composition according to claim 18,wherein the composition contains hydroxypropyl guar in a concentrationof 0.2 to 2.0% (w/v) and boric acid in a concentration of 0.1 to 2.0%(w/v).
 19. A sterile ophthalmic composition according to any one ofclaims 14-18, wherein the composition has a slightly acidic to neutralpH.
 20. A sterile ophthalmic composition according to any one of claims14-18, wherein the composition further comprises a pharmaceuticallyactive agent.
 21. A sterile ophthalmic composition according to any oneof claims 14-18, wherein the composition is adapted for use as an ocularlubricant or artificial tear composition.
 22. A method of lubricatingthe eye, which comprises applying a lubricating amount of a compositionof claim 21 to the eye.
 23. A method of delivering a pharmaceuticalagent to the eye which comprises topically administering to the eye asterile ophthalmic composition comprising a pharmaceutically activeagent, 0.1 to 5% (w/v) of a galactomannan selected from the groupconsisting of guar and derivatives thereof, 0.05 to 5% (w/v) of a boratecompound, and water.
 24. A method according to claim 23, wherein theborate compound is selected from the group consisting of boric acid,sodium borate, potassium borate and combinations thereof.
 25. A methodaccording to claim 24, wherein the galactomannan comprises hydroxypropylguar.
 26. A method according to claim 25, wherein the compositioncontains hydroxypropyl guar in a concentration of 0.2 to 2.0% (w/v), andthe borate compound comprises boric acid in a concentration of 0.1 to2.0% (w/v).
 27. A method according to claim 23, wherein thepharmaceutically active agent is selected from the group consisting of:anti-hypertensive, anti-glaucoma, neuro-protective, anti-allergy,muco-secretagogue, angiostatic, anti-microbial, pain-relieving andanti-inflammatory agents.
 28. A sterile ophthalmic pharmaceuticalcomposition useful as an ocular lubricant or artificial tearcomposition, comprising 0.1 to 3.0% (w/v) of a galactomannan selectedfrom the group consisting of guar and derivatives thereof, 0.1 to 2.0%(w/v) of a borate compound, and water.
 29. A sterile ophthalmiccomposition according to claim 28, wherein the borate compound isselected from the group consisting of boric acid, sodium borate,potassium borate and combinations thereof.
 30. A sterile ophthalmiccomposition according to claim 29, wherein the galactomannan compriseshydroxypropyl guar.
 31. A sterile ophthalmic composition according toclaim 28, wherein the borate compound comprises boric acid.
 32. Asterile ophthalmic composition according to claim 28, wherein thegalactomannan comprises hydroxypropyl guar and the borate compoundcomprises boric acid.
 33. A sterile ophthalmic composition according toany one of claims 28-32, wherein the composition has a slightly acidicto neutral pH.
 34. A sterile ophthalmic composition according to claim33, wherein the composition has a pH of 6 to
 7. 35. A method oflubricating an eye, which comprises topically applying to the eye alubricating amount of a composition according to claim
 34. 36. A methodof lubricating an eye, which comprises topically applying to the eye alubricating amount of a composition according to claim
 33. 37. A methodof lubricating an eye which comprises topically applying to the eye alubricating amount of a composition according to any one of claims28-32.